How does impaired renal function affect the use of linezolid?

From the Guidelines

Linezolid does not require dose adjustment in patients with impaired renal function, as indicated in the 2019 clinical practice guideline by the American Thoracic Society 1. This is because linezolid is primarily metabolized through non-renal pathways. The standard adult dosing of 600 mg daily can be maintained regardless of creatinine clearance, as shown in Table 9 of the guideline, which states "No change needed" for linezolid in patients with reduced renal function 1. However, patients with renal impairment taking linezolid should still be monitored for potential adverse effects such as myelosuppression, lactic acidosis, and peripheral neuropathy, which may occur more frequently with prolonged therapy. Additionally, linezolid has weak, reversible monoamine oxidase inhibitor activity, so caution should be exercised when administering it with serotonergic agents, particularly in patients with end-stage renal disease who may have altered drug clearance for these other medications. Key points to consider when using linezolid in patients with impaired renal function include:

• Monitoring for adverse effects
• Caution with serotonergic agents
• No dose adjustment needed for renal impairment.

From the FDA Drug Label

The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal insufficiency; however, the two primary metabolites of linezolid may accumulate in patients with renal insufficiency, with the amount of accumulation increasing with the severity of renal dysfunction Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal insufficiency However, given the absence of information on the clinical significance of accumulation of the primary metabolites, use of linezolid in patients with renal insufficiency should be weighed against the potential risks of accumulation of these metabolites.

Impaired renal function does not alter the pharmacokinetics of linezolid, but its two primary metabolites may accumulate in patients with renal insufficiency.

• No dose adjustment is recommended for patients with renal insufficiency,
• However, the potential risks of accumulation of the primary metabolites should be considered when using linezolid in these patients 2.

From the Research

Impaired Renal Function and Linezolid Use

Impaired renal function can affect the use of linezolid, an oxazolidinone antibacterial agent. The following points summarize the key aspects of linezolid use in patients with renal impairment:

• Linezolid is mainly cleared by non-renal clearance to two metabolites and renal clearance of the parent compound 3.
• Approximately 50% of an administered dose appears in the urine as the two major metabolites, and approximately 35% appears as parent drug 3.
• In patients with severe renal impairment requiring haemodialysis, the exposure to the two primary metabolites was 7 to 8-fold higher than in patients with normal renal function 3.
• The total apparent oral clearance of linezolid did not change with renal function in subjects not requiring dialysis 4.
• However, subjects with severe renal insufficiency (creatinine clearance, <40 ml/min) and those with end-stage renal disease maintained on hemodialysis had higher concentrations of both metabolites 4.

Dosing Considerations

Dosing considerations for linezolid in patients with renal impairment include:

• No adjustment of the linezolid dosage is needed in subjects with renal dysfunction or subjects on hemodialysis, according to one study 4.
• However, other studies suggest that dose reduction and trough-based therapeutic drug monitoring (TDM) may be necessary to mitigate the risk of thrombocytopenia and anemia in patients with renal impairment 5, 6, 7.
• A proposed dosing regimen includes an initial standard dose for 2 days, followed by a reduced dose of 300 mg every 12 hours, with Cmin-based TDM 5.
• Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with estimated glomerular filtration rate (eGFR) values of <60 ml/min 7.

Adverse Effects

Adverse effects associated with linezolid use in patients with renal impairment include:

• Thrombocytopenia and anemia, which occur more frequently in patients with renal impairment receiving standard linezolid doses 6, 7.
• Severe thrombocytopenia developed as the blood linezolid concentration increased in patients with renal dysfunction 6.
• The platelet count and hemoglobin level decreased as the area under the concentration-time curve from zero to 24 hours (AUC(0-24)) of linezolid increased in patients with renal dysfunction 6.